This is the resubmission of a competitive renewal application for RO1 MH53608, which supports our work on the immediate early gene termed Arc (also termed Arg3.1). During the previous funding period we demonstrated that Arc protein interacts with components of an endocytic pathway that selectively traffics AMPA type glutamate receptors (AMPAR). By this mechanism, Arc can contribute to multiple forms of neural plasticity including homeostatic scaling of AMPAR and long-term depression (LTD). During the next funding period, we will examine the molecular basis for Arc's ability to selectively traffic AMPARs (Aim 1), and test the role of p55PIK as an adaptor that links Arc to GluR1. Aim 2, will examine the hypothesis that phosphorylation of Arc can rapidly inhibit the function of Arc protein in AMPAR trafficking. We will test the contribution of this mechanism in synapse-specific plasticity and homeostatic scaling. Aim 3 will integrate the function of Arc with that of another major endocytic pathway in neurons that is mediated by Pick1, and relate their concerted actions in AMPAR trafficking in multiple forms of plasticity. Aim 4 will explore the hypothesis that Arc functions together with A[unreadable] to regulate neuronal plasticity. A[unreadable] is the processed product of amyloid precursor protein (APP) and is widely studied for its contribution to Alzheimer's disease. Our studies will examine the hypothesis that products of APP processing naturally function to regulate synaptic AMPAR levels in a manner that is controlled by Arc. These studies will advance our understanding of the molecular basis of neural plasticity. PUBLIC HEALTH RELEVANCE: This proposal examines mechanisms that mediate long lasting changes to synapses that are important for learning and memory. The work focuses on a protein termed Arc, which is rapidly up-regulated in neurons as they modify the strength of synapses. Arc regulates a novel endocytosis pathway that mediates trafficking of AMPA type glutamate receptors at synapses. Proposed studies will define the molecular basis of the action of Arc and its role in synaptic plasticity.